Formulation of the Glutamate Hypothesis

Glutamate hypothesis of schizophrenia - Wikipedia

Most human trials have been conducted on cases of Fragile X Syndrome (FXS). The mGluR5 theory of FXS posits that the lack of fragile X mental retardation protein (FMRP) results in excessive glutamatergic signaling via mGluR5 (Bear et al., ). This leads to increased local mRNA translation at the synapse because FMRP is not present to regulate the process. Finally, this weakens the synapse and results in an increased number of longer immature dendritic spines, which could explain the intellectual disability found in FXS patients. This disability is associated with mood and anxiety symptoms and typically present with features that are common in autism spectrum disorder, including delays in speech and language development, impaired theory of mind, and impaired social and emotional processing, as well as repetitive behavior (Garber et al., ). Preliminary and indirect evidence that mGluR5 antagonist can improve sociability in FXS (Burket et al., ) raises hopes that drugs targeting the mGluR5 might be of clinical use in prevalent psychiatric conditions associated with impaired systems for social processes such as autism, schizophrenia, and depression. Furthermore, the observable repetitive behavior phenotype in FXS might suggest a shared pathophysiology among other psychiatric disorders such as obsessive-compulsive disorder (OCD) and addiction.

In this commentary, we review the evidence for and against glutamate as a cotransmitter and discuss the potential role of glutamateâDA corelease in addiction.

Glutamate regulates central nervous system function through the actions of ionotropic and metabotropic receptors. The involvement of glutamate in various psychiatric and medical conditions has been intensively examined. However, earlier work mostly focused on ionotropic glutamate receptors. In contrast to the fast and direct actions of ionotropic receptors, the three groups of metabotropic (mGlu) receptors modify neuronal activity through G-protein coupled signaling. Groups of mGluRs are distinguished by their pharmacological and intracellular signaling properties. mGluR5, which was first cloned in animals in 1992 and a few years later in humans, belongs to group I metabotropic receptors (Olive, ). Its actions are predominantly excitatory (Meldrum, ). Cleva and Olive () described strong links and receptor interactions between mGluR5 and NMDA receptor, suggesting that mGluR5 might also be extensively implicated in mediating neural plasticity as well as learning and memory processes. In addition, there is some evidence that mGluR5 activation enhances GABA, especially in the nucleus accumbens (Hoffpauir and Gleason, ). Thus, it is suggested that metabotropic glutamate receptor activity can modulate excitatory and inhibitory (GABA) signaling pathways. High mGluR5 receptor density was identified primarily in the forebrain regions, striatum, and limbic regions including the amygdala and hippocampus (Swanson et al., ). Using advanced molecular biological techniques to determine mGluR5 mRNA expression in the rodent brain, research determined that regions of the olfactory bulb, dorsal striatum, nucleus accumbens, lateral septum, and hippocampus show the highest levels of mGluR5 expression (Abe et al., ) (See Figure ).

glutamate homeostasis hypothesis of addiction

Many AEDs interact with both the GABA and glutamate neurotransmitter systems, and thus have the potential not only for benefit during withdrawal, but also to prevent relapse to substance use.

NEUROCHEMICAL BASIS OF ADDICTION ASSOCIATED …

Non-competitive antagonists such as PCP and PCP-like compounds bind to a site within the NMDA ion channel at the PCP receptor site (there is also a Mg site within the ion channel). Binding inside the channel is dependent on the state of the ion channel (open or closed). Non-competitive antagonists such as PCP and PCP-like compounds appear to bind only when the channel is open. In the presence of NMDA agonists, binding of PCP to the receptor site is enhanced. Data from MacDonald et al. () provide some clues as to why PCP may have more potent effects than other PCP-like compounds (e.g., ketamine). Basically, the hypothesis is that once a compound binds to the PCP site, the ion channel closes and the trapped molecules cannot escape until the channel reopens. The potency of the drug is determined by its relative rate of escape from the open ion channel. The rate of escape for PCP molecules is 10 times slower than for ketamine—which may account for the higher potency of PCP, since it remains in the channel for longer periods of time (). However, since PCP and PCP-like compounds do not bind exclusively to the PCP receptor, sites such as other inotropic receptors, the metabotropic site, and the sigma site may also be involved in the production of psychotomimetic effects.

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Findings from a large number of preclinical animal trials have determined the effect of mGluR5 antagonist treatment in anxiety. Swanson et al. () reviewed animal studies on drugs targeting the mGluR5 on anxiety-like behaviors. They concluded that mGluR5 antagonistic treatment mostly led to anxiolytic responses in experimental animals. In particular, effects such as reduced fear conditioned freezing, increased shock and punishment acceptance, and increased social interactions were observed. For example, a single dose of 2-methyl-6-(phenylethynyl)pyridine (MPEP) increased the amount of time that rats spent in the open arm of an experimental maze, without affecting planning or motor behavior (Tatarczyńska et al., ). Krystal et al. () reviewed preclinical animal studies that examined mGluR5 antagonists (MTEP, MPEP, fenobam) in mouse models of anxiety. These studies used different outcome measures, such as extinction of fear conditioning and responses in the elevated plus maze, to assess the effectiveness of drug treatments. Of the studies examined, 88.45% reported an anxiolytic effect with mGluR5 antagonists (Krystal et al., ). More recently, another review on anxiety research in animal models that examined the effect of ionotropic and metabotropic glutamate receptor antagonist intervention was published (Riaza Bermudo-Soriano et al., ). Regarding mGluR5, the authors listed 43 animal studies of anxiety, and all but two demonstrated anxiolytic effects.

Recent

5. Dopamine & Glutamate in Addiction - YouTube

In this review, we start with a brief introduction of the glutamate system and mGluR5, and then proceed to evaluate mGluR5 involvement in anxiety and mood disorders, and addiction by comparing previous preclinical trials with recent PET studies. We will then describe an approach how mGluR5 based interventions might be efficient by contributing to changes in learning and social functioning, and by decreasing excitability within various brain regions.

Glutamate Hypothesis of Schizophrenia CUNY WIKI - Duration: 1:18

If glutamate is in fact coreleased with DA as some evidence now suggests, this may have significant implications for advancing our understanding of the interactive role that these 2 neurotransmitters play in cognitive and reward processes.

In the escalation hypothesis of drug addiction, ..

This paper will thus examine if the findings from preclinical research in animals and human psychiatric PET research form a coherent view of mGluR5 involvement in mental disorders. This review will discuss only mGluR5 activity because extensive PET human data are available for this receptor type. mGluR5 delivers a promising target for drug development because a PET tracer can measure mGluR5 binding in humans, thus providing further insight into its functions in humans. Indeed, research suggested that drugs targeting the metabotropic glutamate group I receptors are among the most promising agents currently under development for the treatment of psychiatric conditions (Krystal et al., ).

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“ Although there has been an increase in the scientific knowledge and research on mGluR5, drug development efforts have been relatively unsuccessful (Agid et al., ). Drugs that target the ionotropic receptors usually produce numerous side effects and current drug development strategies have not yet produced selective targets for ionotropic receptors that might reduce potential side effects. For instance, ionotropic receptor antagonists produce side effects in humans that include memory impairment, psychotic episodes, and strokes (Swanson et al., ). The unfavorable side effects might occur because ionotropic glutamate receptors have a ubiquitous distribution, whereas metabotropic receptors are more uneven and selectively distributed (Krystal et al., ). As a result, recent drug development has focused on compounds targeting metabotropic receptors assuming that such drugs will be associated with fewer side effects than those that bind to the fast-acting ionotropic receptors. ”

Glutamate‐Dopamine Cotransmission and Reward Processing …

Gallery The glutamate homeostasis hypothesis of addiction

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Furthermore, glutamateâDA cotransmission has not yet been seriously considered in the context of the neurocircuitry of addiction.

PET is a nuclear, sensitive, and non-invasive medical imaging technique used to image receptor distribution, concentration, and function. To identify human brain receptors, radio labeled receptor ligands (tracers) need to be developed. The scanner device detects gamma rays emitted by the tracer, which is introduced into the body. An mGluR5 PET tracer suitable for human studies was successfully developed at the Paul Scherrer Institute (PSI) in Villigen, Switzerland, and the Swiss Federal Institute of Technology (ETH) in Zurich, Switzerland. ABP688 is a non-competitive and highly selective antagonist, which binds to an allosteric site of the mGluR5. 11C-ABP688 showed high selectivity for mGluR5 and high uptake in receptor-rich brain regions. The first description of these characteristics of 11C-ABP688 in animals is previously published (Ametamey et al., ). We have seen promising results from studies performed in rats that use a beta-probe to estimate the kinetics of this tracer. Furthermore, when we performed the first PET study in humans to estimate the kinetics in humans (Ametamey et al., ) we found results comparable to those found in rat studies (Soares and Law, ). We have now successfully used the developed tracer for research on mGluR5 in healthy volunteers and psychiatric patients. PET techniques deliver information about the relative density of the receptors within the brain area examined. There is no information regarding the concentration of the neurotransmitter (i.e., whether high receptor density might lead to or be the consequence of increased or reduced neurotransmitter action). PET research delivers information regarding receptor level abnormalities in living human patients and thus helps to evaluate which receptors should be targeted with pharmaceutical treatment. On the contrary, Magnetic Resonance Spectroscopy (MRS) provides in vivo biochemical information about the tissue examined (Hasler et al., ) and thus provides information regarding the relative amount of glutamate metabolite in groups of patients. Findings from PET and MRS research can deliver additional evidence to pre-clinical animal studies. Animal research is the state of the art preclinical research method. Various animal models of psychiatric conditions have been established. Animal studies allow testing mechanical models, and testing of new pharmaceuticals in these models to reduce potential harm to humans. One disadvantage for animal research in psychiatry might, however, lie in the development of suitable animal models for different psychiatric conditions, specifically, conditions that involve internal or unique human cognitive aspects might lead to problems. Thus, a new pharmaceutical that shows improvement in animal behavior might not help human internal psychological aspects of the psychiatric condition.